1. Field of the Invention
This invention pertains to the field of solution phase synthesis of oxazoles, particularly 2-arylbenzoxazoles.
2. Background
Oxazoles are a class of pharmaceutically active compounds. Aryloxazoles such as the 2-Arylbenzoxazoles possess the important biaryl pharmacophore and they exhibit a variety of biological activities, including antimicrobial and antitumor properties. For example, a 2-arylbenzoxazole, AJI9561, was recently isolated as a cytotoxic metabolite from the extract of Streptomyces sp. (Sato et al., J. Antibiot. 2001, 54, 102). For other recent examples, see, Temiz et al., Farmaco 1998 53, 337; Aotsuka et al., PCT Int. Appl. WO 98 46,594 1998; Sato et al., Eur. Pat. Appl. EP 806,419 1997; and Deluca et al., Tetrahedron Lett. 1997, 38, 199.
The two most popular methods for synthesizing 2-substituted benzoxazoles are the coupling of carboxylic acids with 2-aminophenols by dehydration catalyzed by a strong acid (Terashima et al., Synthesis 1982, 1484 and references cited therein), and the oxidative cyclization of phenolic Schiff bases, derived from the condensation of 2-aminophenols and aldehydes. The oxidation is effected using various oxidants, such as PhI(OAc)2 (Varma et al., Tetrahedron Lett. 1997, 38, 2621), Mn(OAc)3 (Varma et al., J. Heterocyclic Chem. 1998, 35, 1539), Th+ClO4−(Park et al., Tetrahedron Lett. 1996, 37, 8869), Ba(MnO4)2 (Srivastava et al., Synth. Commun. 1988, 18, 1537), NiO2 (Nakagawa et al., Chem. Pharm. Bull. 1964, 12, 1135) and Pb(OAc)4 (Stephens et al., J. Chem. Soc. 1949, 2971). The first method is of use for making large quantities of pharmaceutical intermediates but typically requires activation of the carboxylic acid under strongly acidic conditions at high temperature. Thus, this method is inappropriate for substrates that include heat-sensitive or acid-labile moieties. The second method generally involves the use of transition metals. The metal byproducts must be removed from the product by filtration or aqueous treatment.
Recently, both solution and solid-phase methods for the synthesis of combinatorial libraries have gained tremendous popularity (see, Thompson et al., Chem. Rev. 1996, 96, 555; Balkenhohl, Angew. Chem. Int. Ed. Engl. 1996, 35, 2288; Hermkens et al., Tetrahedron 1996, 52, 4527; Baldino, C. M. J. Comb. Chem. 2000, 2, 89 and references cited therein). The preparation of compound libraries requires the development of simple and high yielding methods for both the synthesis and purification of the library compounds. Although there have been several reports describing the solid-phase synthesis of benzoxazoles (Wanget al., Tetrahedron Lett. 1997, 38, 6529) there has yet to appear a description of solution-phase libraries of benzoxazoles, presumably due to the lack of any robust procedure for synthesis and purification of these compounds. Accordingly, a need exists for solution-phase synthesis of benzoxazoles. The present invention fulfills this and other needs.